Longer Follow-up Confirms Nivolumab OS Benefit in Nonsquamous NSCLC

Leora Horn, MD

Treatment with the PD-1 inhibitor nivolumab (Opdivo) reduced the risk of death by 28% compared with docetaxel for patients with previously treated nonsquamous non—small cell lung cancer (NSCLC), according to updated findings from the phase III CheckMate-057 study that were presented at the 2015 European Cancer Congress and simultaneously published in The New England Journal of Medicine.^1,2

At a minimum follow-up of 17.2 months, the overall survival (OS) rate with nivolumab was 39% compared with 23% for docetaxel. The median OS with nivolumab was 12.2 versus 9.4 months with docetaxel (HR, 0.72; 95% CI, 0.60-0.88; P <.001). The 1-year progression-free survival (PFS) rates were 19% and 8% and the objective response rates (ORR) were 19% and 12%, with nivolumab and docetaxel, respectively.

Adverse events (AEs) were significantly less frequent with nivolumab compared with docetaxel. The rates of all-grade AEs were 69% and 88%, with nivolumab and docetaxel. Grade 3/4 AEs occurred in 10% of patients treated with nivolumab compared with 54% for docetaxel.

“These longer term survival results for nivolumab in advanced, nonsquamous non—small cell lung cancer support the potential for this immuno-oncology agent in treating lung cancer patients,” lead investigator Leora Horn, MD, from the Vanderbilt-Ingram Cancer Center, said in a statement. “CheckMate-057 builds upon its critical findings and now, data show a sustained survival benefit for nivolumab in this hard-to-treat disease that is incredibly encouraging for oncologists, and most importantly, for our patients.”

In the open-label CheckMate-057 trial, 582 patients with advanced nonsquamous NSCLC were randomized after the failure of platinum-based doublet chemotherapy to nivolumab at 3 mg/kg IV every 2 weeks (n = 292) or docetaxel at 75 mg/m² intravenously every 3 weeks (n = 290). The median patient age was 62 years and most had an ECOG performance status of 1. A median of 6 doses of nivolumab were administered versus 4 doses of docetaxel.

Prior maintenance with bevacizumab, pemetrexed, or erlotinib was allowed, as was TKI therapy for those with a known EGFR mutations or ALK translocation. Forty-percent and 38% of patients in the nivolumab and docetaxel arms, respectively, had received prior maintenance therapy. In the nivolumab arm, 15% of patients were EGFR-positive and 4% were ALK-positive, with comparable rates of 13% and 3%, respectively, in the docetaxel group.

For those who received nivolumab the median time to response was 2.1 months compared with 2.6 months with docetaxel. The median duration of response (DoR) was 17.2 months with nivolumab and 5.6 months with docetaxel. Subsequent therapies were received by 42% in the nivolumab arm and by 50% with docetaxel.

The median PFS was 2.3 months with nivolumab compared with 4.2 months with docetaxel (HR, 0.92; 95% CI, 0.77-1.1; P = .39). This lower numerical median PFS with nivolumab could be explained by pseudoprogression. After initial progression 71 patients (24%) in the nivolumab arm continued to receive treatment, with 16 (23%) having a nonconventional response.

In patients with quantifiable PD-L1 expression (n = 455; 78%), there was a greater benefit seen with nivolumab compared with docetaxel for those with ≥1% staining. However, in those with expression <1% those treated with docetaxel (n = 101) had an ORR of 15% compared with 9% with nivolumab (n = 108).

In those with the highest expression of PD-L1 (≥10%), the ORR with nivolumab was 37% with a median DoR of 16 months compared with an ORR of 13% and a DoR of 5.6 months with docetaxel (odds ratio, 4.1; 95% CI, 1.8-10.1). In those with PD-L1 expression ≥1% the ORR was 31% and the DoR was 16 months with nivolumab (n = 123) versus an ORR of 12% and a DoR of 5.6 months with docetaxel (n = 123).

The most common grade 3/4 AEs with nivolumab were fatigue, nausea, and diarrhea, at 1% each. Twenty-seven percent of patients in the docetaxel arm had grade 3/4 neutropenia versus 0 in the nivolumab arm. Toxicity-related discontinuations occurred in 5% of patients receiving nivolumab compared with 15% of those treated with chemotherapy.

“The 18-month data from CheckMate-057 reinforce the potential for Opdivo, across PD-L1 expression levels, to offer patients durable overall survival benefit with lower incidence of serious adverse events versus chemotherapy,” Michael Giordano, MD, senior vice president, head of Development, Oncology at Bristol-Myers Squibb, the company developing the drug, said in a statement.

On September 2, 2015, the FDA granted nivolumab both a breakthrough therapy designation and a priority review for patients with previously treated nonsquamous NSCLC. Both designations were based on data from the phase III CheckMate-057 trial. Under this expedited review process, the FDA’s decision deadline is January 2, 2016.

The FDA approved nivolumab for patients with squamous NSCLC in March 2015. Similar 18-month data for patients with squamous NSCLC were presented at the 2015 World Conference on Lung Cancer (WCLC) from the phase III CheckMate-017 study.³ In this study, 272 pretreated patients with squamous NSCLC were randomized to receive nivolumab at 3 mg/kg every 2 weeks (n = 135) or docetaxel at 75 mg/m² every 3 weeks (n = 137).

At the analysis, the OS rate with nivolumab was 28% versus 13% with docetaxel in previously treated patients with squamous NSCLC. The median OS with nivolumab was 9.2 versus 6.0 months for docetaxel (HR, 0.62; 95% CI, 0.48-0.81; P = .0004).

In a second study presented at WCLC, a similar 18-month OS rate of 27% was seen for pretreated patients with squamous NSCLC.⁴ In this smaller single-arm phase II trial, labeled CheckMate-063, the median OS was 8.1 months (95% CI, 6.1-10.9).

Prior to lung cancer indications, the FDA approved nivolumab for the treatment of patients with unresectable or metastatic melanoma following treatment with ipilimumab or a BRAF inhibitor. Numerous clinical trials continue to assess the medication across clinical indications.

References:

1. Horn L, Brahmer J, Reck M, et al. Phase 3, randomized trial (CheckMate 057) of nivolumab (NIVO) vs docetaxel (DOC) in advanced non-squamous (non-SQ) non-small cell lung cancer (NSCLC): Subgroup analyses and patient reported outcomes (PROs). Presented at: 2015 European Cancer Congress; September 25-29; Vienna, Austria. Abstract 3010.
2. Borghaei H, Paz-Ares L, Horn L, et al. Nivolumab versus Docetaxel in Advanced Nonsquamous Non—Small-Cell Lung Cancer [published online September 27, 2015]. N Engl J Med. doi:10.1056/NEJMoa1507643.
3. Reckamp K, Spigel DR, Rizvi NA, et al. Phase 3, randomized trial (CheckMate 017) of nivolumab (NIVO) vs docetaxel in advanced squamous (SQ) cell non-small cell lung cancer (NSCLC). Presented at: 16th World Conference on Lung Cancer; September 6-9; Denver, CO. Abstract 736.
4. Horn L, Rizvi NA, Mazières J, et al. Longer-term follow-up of a phase 2 study (CheckMate 063) of nivolumab in patients with advanced, refractory squamous non-small cell lung cancer. Presented at: 16th World Conference on Lung Cancer; September 6-9; Denver, CO. Abstract 828.

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